Antipsychotic Agents & Lithium

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3 ANTIPSYCHOTIC AGENTS Introduction HistoryAntipsychotic & neurolepticSchizophrenia, psychoses & agitated statesHistoryReserpine and chlorpromazine for more than 50 yearsThe number of patients hospitalized has decreasedSchizophrenia is now recognized as a biologic illnessNature of Psychosis & SchizophreniaThe term "psychosis" denotes a variety of mental disordersSchizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance

4 THE DOPAMINE HYPOTHESIS1) many antipsychotic drugs strongly block postsynaptic D2 receptors in the central nervous system, especially in the mesolimbic-frontal system;(2) drugs that increase dopaminergic activity, such as levodopa (a precursor), amphetamines (releasers of dopamine), and apomorphine (a direct dopamine receptor agonist), either aggravate schizophrenia or produce psychosis de novo in some patients(3) dopamine receptor density has been found postmortem to be increased in the brains of schizophrenics who have not been treated with antipsychotic drugs;(4) positron emission tomography (PET) has shown increased dopamine receptor density in both treated and untreated schizophrenics when compared with such scans of nonschizophrenic persons(5) successful treatment of schizophrenic patients has been reported to change the amount of homovanillic acid (HVA), a metabolite of dopamine, in the cerebrospinal fluid, plasma, and urine

5 THE DOPAMINE HYPOTHESIS ?They are only partially effective for most and ineffective for some patientsAntagonists of the NMDA receptor such as phencyclidine, when administered to nonpsychotic subjects, produce much more "schizophrenia-like" symptoms than do dopamine agonists.Several of the atypical antipsychotic drugs have much less effect on D2 receptors and yet are effective in schizophrenia

6 Chemical Types A. PHENOTHIAZINE DERIVATIVESAliphatic derivatives (eg, chlorpromazine) and piperidine derivatives (eg, thioridazine) are the least potent.Piperazine derivatives are more potent (effective in lower doses) but not necessarily more efficacious.The piperazine derivatives are also more selective in their pharmacologic effectsB. THIOXANTHENE DERIVATIVESThiothixeneIn general, these compounds are slightly less potent than their phenothiazine analogs.C. BUTYROPHENONE DERIVATIVESHaloperidol is the most widely used, has a very different structureThe butyrophenones and congeners tend to be more potent and to have fewer autonomic effects but greater extrapyramidal effectsD. MISCELLANEOUS STRUCTURESThe newer drugspimozide, molindone, loxapine, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole

22 Pharmacokinetics ABSORPTION AND DISTRIBUTIONMost readily but incompletely absorbedMany undergo significant first-pass metabolismMost antipsychotic drugs are highly lipid-soluble and protein- bound (92-99%).They have large volumes of distribution (usually > 7 L/kg).They generally have a much longer clinical duration of action than would be estimated from their plasma half-livesFull relapse may not occur until 6 weeks or more after discontinuationMost are almost completely metabolizedSome metabolites retain activity but are weakThe sole exception is mesoridazinechlorpromazine and thioridazine have systemic availability of 25% to 35%, whereas haloperidol, which is less likely to be metabolized, has an average systemic availability of about 65%Metabolites of chlorpromazine may be excreted in the urine weeks after the last dose of chronically administered drug.

25 OTHER EFFECTSMost antipsychotic drugs cause unpleasant subjective effects in nonpsychotic individualsSome of the neuroleptic agents lower the seizure thresholdGalactorrhea, false-positive pregnancy tests, and increased libido have been reported in womenMen have experienced decreased libido and gynecomastiaAbnormal ECGs have been recorded, especially with thioridazine

26 PSYCHIATRIC INDICATIONSSchizophrenia is the primary indicationMany patients show little response and virtually none show a complete responseThey also indicated for schizoaffective disordersThe psychotic aspects of the illnessThe manic phase in bipolar affective disorder often requires treatment with antipsychotic agents in severeolanzapine has been approved for this indicationWith antidepressants, psychotic depression

27 PSYCHIATRIC INDICATIONSNonmanic excited states may also be managed by antipsychotics, often in combination with benzodiazepinesTourette's syndromeDisturbed behavior in patients with Alzheimer's diseaseThey are not indicated for the treatment of various withdrawal syndromes, eg, opioid withdrawalIn small doses antipsychotics have been promoted (wrongly) for the relief of anxiety associated with minor emotional disordersTourette syndrome (also called Tourette's syndrome, Tourette's disorder, Gilles de la Tourette syndrome, GTS or, more commonly, simply Tourette's or TS) is an inherited neuropsychiatric disorder with onset in childhood, characterized by the presence of multiple physical (motor) tics and at least one vocal (phonic) tic; these tics characteristically wax and wane. Tourette's is defined as part of a spectrum of tic disorders, which includes transient and chronic tics.

28 NONPSYCHIATRIC INDICATIONSMost older antipsychotic drugs, with the exception of thioridazine, have a strong antiemetic effectDopamine receptor blockade, both centrally (in the chemoreceptor trigger zone of the medulla) and peripherally (on receptors in the stomach)Some drugs, such as prochlorperazine and benzquinamide, are promoted solely as antiemeticsPhenothiazines (shorter side chains) have considerable H1-blocker and have been used for relief of pruritus or, in the case of promethazine, as preoperative sedativesThe butyrophenone droperidol is used in combination with an opioid, fentanyl, in neuroleptanesthesia

29 DRUG CHOICEChoice is based mainly on differences in adverse effects and possible differences in efficacyNew antipsychotic drugs have been shown in some trials to be more effective than older ones for treating negative symptoms (emotional blunting, social withdrawal, lack of motivation)Several of the newer antipsychotics, including clozapine, risperidone, and olanzapine, show superiority over haloperidol in terms of overall response in some controlled trialsOlder drugs that offer intramuscular formulations for acute and chronic treatment

31 BenzisoxazoleRisperidoneBroad efficacy; little or no extrapyramidal system dysfunction at low dosesExtrapyramidal system dysfunction and hypotension with higher dosesThienobenzodiazepineOlanzapineEffective against negative as well as positive symptoms; little or no extrapyramidal system dysfunctionWeight gain; dose-related lowering of seizure thresholdDibenzothiazepineQuetiapineSimilar to olanzapine; perhaps less weight gainMay require high doses if there is associated hypotension; short t1/2 and twice-daily dosingDihydroindoloneZiprasidonePerhaps less weight gain than clozapine, parenteral form availableQTc prolongationDihydrocarbostyrilAripiprazoleLower weight gain liability, long half-life, novel mechanism potentialUncertain, novel toxicities possible

32 DOSAGEThe range of effective dosages among various antipsychotics is quite broadSome patients who fail to respond to one drug may respond to anotherDiffering profiles of receptor actions of the various drugsPatients who have become refractory to two or three antipsychotic agents given in substantial doses now become candidates for treatment with clozapinein dosages up to 900 mg/d, salvages about 30-50% of patients previously refractory to 60 mg/d of haloperidolRisperidone does not appear to substitute for clozapine, although reports are mixed

33 PARENTERAL PREPARATIONSWell-toleratedHigh-potency older drugsRapid initiation of treatment as well as for maintenance treatment in noncompliant patientsDoses should be only a fraction of what might be given orallyFluphenazine decanoate 25 mgHaloperidol decanoate 5 mgFlupenthixol 20 mg

34 DOSAGE SCHEDULESFirst, titrating to an effective dosage in divided daily dosesAfter an effective daily dosage has been defined for an individual patient, doses can be given less frequentlyOnce-daily doses, usually given at night

35 MAINTENANCE TREATMENTA very small minority require no further drug therapy for prolonged periodsIn most cases, the choice is between "as needed" increased doses or addition of other drugsThe choice depends on social factors such as the availability of family or friends familiar with the symptoms of early relapse and ready access to care

36 DRUG COMBINATIONS Use of combinations is widespreadTCAs or, more often, SSRIsLithium or valproic acid is sometimes added to antipsychotic agents with benefit to patients who do not respond to the latter drugs alonemisdiagnosed cases of mania or schizoaffective disorder?Sedative drugs may be added for relief of anxiety or insomnia not controlled by antipsychotics

37 ADVERSE REACTIONS A. BEHAVIORAL EFFECTS B. NEUROLOGIC EFFECTSPseudodepression that may be due to drug-induced akinesiaB. NEUROLOGIC EFFECTSEPS: with older drugs and early during treatmentParkinson's syndrome, akathisia (uncontrollable restlessnessArtanSelf-limiting, so that an attempt to withdraw antiparkinsonism drugs should be made every 3-4 monthsAcute dystonic reactions (spastic retrocollis or torticollis)DiphenhydramineTardive dyskinesia20-40% of chronically treated patientsSwitch to one of the newer atypical agentsEliminate all drugs with central anticholinergic action (TCAs )

39 ADVERSE REACTIONS C. AUTONOMIC NERVOUS SYSTEM EFFECTSD. METABOLIC AND ENDOCRINE EFFECTSWeight gain is very common, especially with clozapine and olanzapineHyperprolactinemia in women results in the amenorrhea- galactorrhea syndrome and infertility; in men, loss of libido, impotence, and infertility may resultE. TOXIC OR ALLERGIC REACTIONSclozapine causes agranulocytosis in 1-2%weekly blood counts for the first 6 months of treatment and every 3 weeks thereafterF. OCULAR COMPLICATIONSChlorpromazine deposits in the cornea and lensThioridazine  retinal deposits  browning of vision

40 ADVERSE REACTIONS G. CARDIAC TOXICITYOverdoses of thioridazine are associated with major ventricular arrhythmias, cardiac conduction block, and sudden deathH. USE IN PREGNANCY; DYSMORPHOGENESISRelatively safe in pregnancy (must be decided individually)I. NEUROLEPTIC MALIGNANT SYNDROMEIn patients who are extremely sensitive to the extrapyramidal effects of antipsychotic agentsMuscle rigidity (Creatine kinase isozymes are usually elevated)Sweating is impaired by anticholinergicsThe stress leukocytosis and high feverAutonomic instability, with altered blood pressure and pulse rateVigorous treatment with antiparkinsonism drugs early in the courseMuscle relaxants, particularly diazepam, are often useful, dantrolen and bromocriptine, have been reported to be helpfulIf fever is present, cooling by physical measures should be tried

41 DRUG INTERACTIONSAntipsychotics produce more important pharmacodynamic than pharmacokinetic interactionsThioridazine and ziprasidone-quinidine-like action

42 OVERDOSESPoisonings with antipsychotics (unlike TCAs) are rarely fatal, with the exception of those due to mesoridazine and thioridazineDrowsiness proceeds to coma, with an intervening period of agitationNeuromuscular excitability may be increased and proceed to convulsionsPupils are miotic, and deep tendon reflexes are decreasedHypotension and hypothermia are the rule, though fever may be present later in the course.

44 MOOD-STABILIZING DRUGSLithium carbonateAntimanic or "mood-stabilizing" agentCarbamazepine efective but not approvedValproate has recently been approvedAtypical antipsychotics, beginning with olanzapine, are being investigated and approved as antimanic agents and potential mood stabilizersGrandiosity, bellicosity, paranoid thoughts, and overactivityBipolar disorder has a strong familial component

47 PHARMACODYNAMICS (1) effects on electrolytes and ion transportIt can substitute for sodium in generating action potentials(2) effects on neurotransmitters and their release(3) effects on second messengers and intracellular enzymes that mediate transmitter action

49 Bipolar Affective DisorderUntil recently, lithium carbonate was the universally preferred treatment for bipolar disorderSlow onset of action of lithiumThe overall success is 80% but lower in hospitalized patientsIn maintenance it is 60% effective overall but less in severely ill patientsThe depressive phaseTCA  precipitation of maniaSSRIs  limited efficacyBupropion  may induce mania at higher dosesMAO  for some patientsLamotrigine  effective for many patients

50 Other ApplicationsRecurrent endogenous depression with a cyclic pattern is controlled by either lithium or imipramineSchizoaffective disorder -a mixture of schizophrenic symptoms and depression or excitement- is treated with antipsychotic drugs alone or combined with lithium.Antidepressants are added if depression is presentIn schizophrenia, adding it to an antipsychotic may salvage an otherwise treatment-resistant patientCarbamazepine may work equallyWith TCAs or SSRIs in patients with unipolar depression who do not respond fully to monotherapy with the antidepressant (low dose)

51 Monitoring TreatmentMeasurements are customarily taken hours after the last doseFirst TDM obtained about 5 days after the start of treatmentSimple arithmetic should produce the desired levelOnce the desired concentration has been achieved, levels can be measured at increasing intervals unless the schedule is influenced by intercurrent illness or the introduction of a new drug into the treatment program

52 MAINTENANCE TREATMENTPatients who have one or more episodes of illness per year are candidates for maintenance treatmentAlthough some patients can be maintained with serum levels as low as 0.6 mEq/L, the best results have been obtained with higher levels, such as 0.9 mEq/L

53 Drug InteractionsRenal clearance of lithium is reduced about 25% by diuretics (eg, thiazides), and doses may need to be reduced by a similar amountA similar reduction in lithium clearance has been noted with several of the newer NSAIDsNot reported for either aspirin or acetaminophenAll neuroleptics (except to clozapine and the newer antipsychotics) may produce more severe EPS when combined with lithium

55 ADVERSE EFFECTS & COMPLICATIONSCARDIAC ADVERSE EFFECTSThe bradycardia-tachycardia ("sick sinus") syndrome is a definite contraindication to the use of lithium because the ion further depresses the sinus nodeUSE DURING PREGNANCYRenal clearance of lithium increases during pregnancy and needs dose reduction after deliveryLithium toxicity in newborns is manifested by lethargy, cyanosis, poor suck and Moro reflexes, and perhaps hepatomegalyIn breast milk one-third to one-half that of serumMISCELLANEOUS ADVERSE EFFECTSTransient acneiform eruptions have been noted early in lithium treatmentFolliculitis is less dramatic and probably occurs more frequentlyLeukocytosis by leukopoiesisThe Moro reflex is an infantile reflex normally present in all infants/newborns up to 4 or 5 months of age as a response to a sudden loss of support, when the infant feels as if it is falling. It involves 3 distinct components:spreading out the arms (abduction)unspreading the arms (adduction)crying (usually)The primary significance of the Moro reflex is in evaluating integration of the central nervous system. It is distinct from the startle reflex,[1] and is believed to be the only unlearned fear in human newborns

56 OVERDOSESCommonSome change in the patient's status, such as diminished serum sodium, use of diuretics, or fluctuating renal functionAny value over 2 mEq/L must be considered as indicating likely toxicityBoth peritoneal dialysis and hemodialysis are effective

57 VALPROIC ACID Gabapentin is not effectiveEquivalent efficacy to that of lithium during the early weeks of treatmentIn some patients who have failed to respond to lithiumIts side-effect profile is such that one can rapidly increase the dosageNausea being the only limiting factor in some patientsAn appropriate first-line treatment for maniaIs it effective as lithium in maintenance treatment ?Combining valproic acid and lithium in patients who do not fully respond to either agent alone

58 CARBAMAZEPINE Oxcarbazepine is not effectiveCarbamazepine may be used to treat acute mania and also for prophylactic therapyAdverse effects are generally no greater and sometimes less than those associated with lithiumIt may be used alone or, in refractory patients, in combination with lithium or, rarely, valproateBlood dyscrasias not seen with its use as a mood stabilizerOverdoses are a major emergency and should generally be managed like overdoses of TCAs